title: Abnormal Ca(2+) homeostasis, atrial arrhythmogenesis, and sinus node dysfunction in murine hearts modeling RyR2 modification.
abstract: Ryanodine receptor type 2 (RyR2) mutations are implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT) thought to result from altered myocyte Ca(2+) homeostasis reflecting inappropriate "leakiness" of RyR2-Ca(2+) release channels arising from increases in their basal activity, alterations in their phosphorylation, or defective interactions with other molecules or ions. The latter include calstabin, calsequestrin-2, Mg(2+), and extraluminal or intraluminal Ca(2+). Recent clinical studies additionally associate RyR2 abnormalities with atrial arrhythmias including atrial tachycardia (AT), fibrillation (AF), and standstill, and sinus node dysfunction (SND). Some RyR2 mutations associated with CPVT in mouse models also show such arrhythmias that similarly correlate with altered Ca(2+) homeostasis. Some examples show evidence for increased Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2. A homozygotic RyR2-P2328S variant demonstrates potential arrhythmic substrate resulting from reduced conduction velocity (CV) in addition to delayed afterdepolarizations (DADs) and ectopic action potential (AP) firing. Finally, one model with an increased RyR2 activity in the sino-atrial node (SAN) shows decreased automaticity in the presence of Ca(2+)-dependent decreases in I Ca, L and diastolic sarcoplasmic reticular (SR) Ca(2+) depletion.
authors.affiliation: Department of Paediatrics, Institute of Shaanxi Province Children's Cardiovascular Diseases, The Shaanxi Provincial People's Hospital of Xi'an Jiaotong University Xi'an, PR of China ; Faculty of Medicine and Human Sciences, Institute of Cardiovascular Sciences, University of Manchester Manchester, UK.
authors.forename: Yanmin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Gareth D K
authors.initials: GD
authors.lastname: Matthews
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Christopher L-H
authors.initials: CL
authors.lastname: Huang
keywords: RyR2; atrial arrhythmias; mouse models; mutation; sinus node dysfunction